U.S. patent application number 13/126395 was filed with the patent office on 2011-08-25 for highly purified polylactic acid or a derivative thereof, a salt of the same, and purification method thereof.
This patent application is currently assigned to SAMYANG CORPORATION. Invention is credited to Bong Oh Kim, Min Hyo Seo.
Application Number | 20110207834 13/126395 |
Document ID | / |
Family ID | 42153039 |
Filed Date | 2011-08-25 |
United States Patent
Application |
20110207834 |
Kind Code |
A1 |
Kim; Bong Oh ; et
al. |
August 25, 2011 |
HIGHLY PURIFIED POLYLACTIC ACID OR A DERIVATIVE THEREOF, A SALT OF
THE SAME, AND PURIFICATION METHOD THEREOF
Abstract
Disclosed are a highly purified polylactic acid or a derivative
thereof, or a salt thereof, and a method for purifying the same.
The polylactic acid or a derivative thereof, or a salt thereof may
be applied to various medical and drug carrier systems, or the
like.
Inventors: |
Kim; Bong Oh; (Daejeon,
KR) ; Seo; Min Hyo; (Seo-gu, KR) |
Assignee: |
SAMYANG CORPORATION
Seoul
KR
|
Family ID: |
42153039 |
Appl. No.: |
13/126395 |
Filed: |
June 23, 2009 |
PCT Filed: |
June 23, 2009 |
PCT NO: |
PCT/KR2009/003366 |
371 Date: |
April 27, 2011 |
Current U.S.
Class: |
514/785 ;
560/179 |
Current CPC
Class: |
C08G 63/90 20130101;
A61P 43/00 20180101; C08G 63/08 20130101 |
Class at
Publication: |
514/785 ;
560/179 |
International
Class: |
A61K 47/34 20060101
A61K047/34; A61P 43/00 20060101 A61P043/00; C07C 69/68 20060101
C07C069/68 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 7, 2008 |
KR |
10-2008-0110348 |
Claims
1. A method for purifying a polylactic acid or a derivative
thereof, or a salt thereof, comprising: dissolving a polylactic
acid or a derivative thereof, or a salt thereof into a
water-miscible organic solvent; adding water or an aqueous alkali
metal salt solution to the solution of the polymer dissolved in the
organic solvent, followed by mixing; subjecting the mixture to
phase separation to remove water and to recover the organic solvent
layer; and removing the organic solvent from the organic solvent
layer to recover the polymer.
2. The method for purifying a polylactic acid or a derivative
thereof, or a salt thereof according to claim 1, wherein the
water-miscible organic solvent is acetone or acetonitrile.
3. The method for purifying a polylactic acid or a derivative
thereof, or a salt thereof according to claim 1, wherein the alkali
metal salt is at least one metal(s) salt selected from the group
consisting of sodium bicarbonate, sodium carbonate, potassium
carbonate and lithium carbonate.
4. The method for purifying a polylactic acid or a derivative
thereof, or a salt thereof according to claim 1, wherein the mixing
is carried out by agitating the mixture at 40-100.degree. C. for 10
minutes to 24 hours.
5. The method for purifying a polylactic acid or a derivative
thereof, or a salt thereof according to claim 1, wherein the phase
separation is carried out by adding a salt to the mixture so that
the mixture is separated into an organic solvent layer and an
aqueous layer.
6. The method for purifying a polylactic acid or a derivative
thereof, or a salt thereof according to claim 5, wherein the salt
is sodium chloride or potassium chloride.
7. The method for purifying a polylactic acid or a derivative
thereof, or a salt thereof according to claim 1, which further
comprises, after the removing the organic solvent from the organic
layer to recover the polymer: dissolving the recovered polymer into
an anhydrous organic solvent, followed by filtering, to obtain a
polymer-containing organic solvent; and removing the anhydrous
organic solvent from the polymer-containing organic solvent.
8. The method for purifying a polylactic acid or a derivative
thereof, or a salt thereof according to claim 7, wherein the
anhydrous organic solvent is anhydrous acetone or anhydrous
acetonitrile.
9. The method for purifying a polylactic acid or a derivative
thereof, or a salt thereof according to claim 1, wherein the
polylactic acid or a derivative thereof, or a salt thereof
comprises a monomer represented by Chemical Formula 1: ##STR00002##
wherein Y represents H, methyl or phenyl; and A represents an
integer from 5 to 300.
10. The method for purifying a polylactic acid or a derivative
thereof, or a salt thereof according to claim 1, wherein the
polylactic acid or a derivative thereof, or a salt thereof is
represented by Chemical Formula 2 or 3:
HO--[R.sup.1].sub.l--[R.sup.2].sub.m--C(.dbd.O)--O-M [Chemical
Formula 2]
[HO--[R.sup.1].sub.l--[R.sup.2].sub.m--C(.dbd.O)--O-].sub.n-A
[Chemical Formula 3] wherein R.sup.1 represents
--C(.dbd.O)--O--CHZ--; R.sup.2 represents --C(.dbd.O)--O--CHY--,
--C(.dbd.O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2-- or
--C(.dbd.O)--O--CH.sub.2CH.sub.2OCH.sub.2--; Z and Y independently
represent H, methyl or phenyl; l and m represent an integer from 0
to 150, with the proviso that both cannot represent 0 at the same
time; M represents H, Na, K or Li; A represents a diol or a polyol
compound containing 3-12 hydroxyl groups; and n represents an
integer from 2 to 12 and is the same as the number of hydroxyl
groups contained in A.
11. A Polylactic acid or a derivative thereof, or a salt thereof,
which has a lactone monomer content of 1.0 wt % or less and a
content of metal in an organometal catalyst of 50 ppm or less.
12. The polylactic acid or a derivative thereof, or a salt thereof
according to claim 11, which is at least one compound(s) selected
from the group consisting of polylactide, polyglycolide,
polymandelic acid, polycaprolactone, polydioxane-2-one, copolymers
thereof, polyaminoacids, polyorthoesters and polyanhydrides.
13. The polylactic acid or a derivative thereof, or a salt thereof
according to claim 11, which has a number average molecular weight
of 500-20,000 daltons.
14. A pharmaceutical composition comprising the polylactic acid or
a derivative thereof, or a salt thereof purified by the method as
defined in claim 1.
15. A pharmaceutical composition comprising the polylactic acid or
a derivative thereof, or a salt thereof as defined in claim 11.
Description
TECHNICAL FIELD
[0001] This disclosure relates to a polylactic acid or a derivative
thereof, or a salt thereof with high purity, and a method for
purifying the same.
BACKGROUND ART
[0002] Polylactic acid is one of biodegradable polymers, and has
been applied to drug carriers in various forms because it has
excellent biocompatibility and it is hydrolyzed into lactic acid
non-harmful to the human body. Polylactic acid derivatives
including a polylactic acid have various properties depending on
molecular weight. For example, a polylactic acid derivative having
a molecular weight of 2000 daltons or higher is not soluble in
water, and thus has been developed into microspheres,
nanoparticles, polymeric gels and implant agents.
[0003] In addition, polylactic acid derivatives used as drug
carriers may be modified in terms of molecular weight and copolymer
constitution to control drug release rate. In controlling drug
release rate, purity of a polylactic acid derivative plays an
important role. During the polymerization of a polymer from
monomers, unreacted monomers may remain in the polymer to decrease
the purity of the polylactic acid derivative. If the content of
unreacted monomers is high, the polylactic acid derivative has a
broad molecular weight distribution. As a result, administration of
a low-molecular weight polymer molecule into the human body may
cause excessive drug release at the initial time. Moreover, while
the remaining monomers are decomposed, pH decreases and the polymer
decomposition rate increases. This makes it difficult to accomplish
prolonged drug release.
[0004] According to the related art, a polylactic acid is purified
by a solvent/non-solvent method. The method is advantageous in that
a solidified polymer may be obtained, when the polymer has a high
molecular weight or when preparing an L,L-polylactic acid
derivative. However, when the polymer has a low molecular weight or
when preparing non-crystalline D,L-polylactic acid derivatives,
gel-like precipitate is generated upon settling in a non-solvent,
making it difficult to purify the polymer.
[0005] Particularly, in the case of D,L-polylactic acid with a low
molecular weight, precipitation of its acetone solution in
distilled water causes generation of gel-like precipitate. Such
gel-like precipitate hardly allows moisture removal even when
subjected to vacuum drying. Thus, removing moisture needs a long
time. In addition, under the high-temperature vacuum condition,
condensation polymerization may occur, making it difficult to
control the molecular weight. Further, under the same condition,
lactide monomers may be produced.
[0006] Additionally, when the polymer has a high molecular weight
or when preparing crystalline L,L-polylactic acid, solidified
polylactic acid may be obtained through the above-mentioned
solvent/non-solvent method. However, during the purification based
on the solvent/non-solvent method, the monomers and an organometal
catalyst may co-precipitate in the non-solvent and be not removed
effectively therefrom.
[0007] Meanwhile, a method for purifying D,L-polylactic acid with a
low molecular weight by liquid-liquid phase separation is also
known. After the polymerization, the polymer is dissolved in
methanol or ethanol under heating. Then, the polymer solution is
refrigerated at a temperature of -78.degree. C. so that phase
separation occurs. Polylactic acid with a low molecular weight is
dissolved in the upper organic solvent layer, while polylactic acid
with a high molecular weight is solidified in the lower layer. The
lower layer is separated and the solvent is distilled off to remove
the monomers and oligomers. In this manner, highly purified
D,L-polylactic acid having a narrow molecular weight distribution
is provided. However, the lactide monomers produced during the
polymerization is dissolved in an alcohol solvent at high
temperature but recrystallized therein at low temperature.
Therefore, the monomers are not removed effectively from
D,L-polylactic acid even after carrying out the above method.
DISCLOSURE
Technical Problem
[0008] Provided is a method for effectively purifying a polylactic
acid or a derivative thereof, or a salt thereof.
[0009] Also provided is a polylactic acid or a derivative thereof,
or a salt thereof with high purity.
[0010] Further provided is a pharmaceutical composition including a
polylactic acid or a derivative thereof, or a salt thereof with
high purity.
Technical Solution
[0011] Disclosed herein is a polylactic acid or a derivative
thereof, or a salt thereof with high purity. Disclosed herein too
is a method for purifying the same. More particularly, the method
includes: dissolving a polylactic acid or a derivative thereof, or
a salt thereof into a water-miscible organic solvent; adding water
or an aqueous alkali metal salt solution to the solution of polymer
dissolved in the organic solvent, followed by mixing; subjecting
the mixture to phase separation to remove water and to recover the
organic solvent layer; and removing the organic solvent from the
organic solvent layer to recover the polymer. In addition, the
polylactic acid or a derivative thereof, or a salt thereof
disclosed herein has a lactone monomer content of 1.0 wt % or less
and a content of metal in an organometal catalyst of 50 ppm or
less.
Advantageous Effects
[0012] According to the method disclosed herein, it is possible to
obtain a highly purified polylactic acid or a derivative thereof,
or a salt thereof, from which unreacted monomers, oligomers, and
metals are removed effectively.
DESCRIPTION OF DRAWINGS
[0013] The above and other aspects, features and advantages of the
disclosed exemplary embodiments will be more apparent from the
following detailed description taken in conjunction with the
accompanying drawings in which:
[0014] FIG. 1 is the .sup.1H-NMR spectrum of D,L-polylactic acid
obtained from Preparation Example 1;
[0015] FIG. 2 is the .sup.1H-NMR spectrum of D,L-polylactic acid
purified according to Comparative Example 1;
[0016] FIG. 3 is the .sup.1H-NMR spectrum of D,L-polylactic acid
purified according to Example 1; and
[0017] FIG. 4 is the .sup.1H-NMR spectrum of sodium salt of
D,L-polylactic acid purified according to Example 2.
MODE FOR INVENTION
[0018] Exemplary embodiments now will be described more fully
hereinafter with reference to the accompanying drawings, in which
exemplary embodiments are shown. This disclosure may, however, be
embodied in many different forms and should not be construed as
limited to the exemplary embodiments set forth therein. Rather,
these exemplary embodiments are provided so that this disclosure
will be thorough and complete, and will fully convey the scope of
this disclosure to those skilled in the art. In the description,
details of well-known features and techniques may be omitted to
avoid unnecessarily obscuring the presented embodiments.
[0019] The terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting of
this disclosure. As used herein, the singular forms "a", "an" and
"the" are intended to include the plural forms as well, unless the
context clearly indicates otherwise. Furthermore, the use of the
terms a, an, etc. does not denote a limitation of quantity, but
rather denotes the presence of at least one of the referenced item.
It will be further understood that the terms "comprises" and/or
"comprising", or "includes" and/or "including" when used in this
specification, specify the presence of stated features, regions,
integers, steps, operations, elements, and/or components, but do
not preclude the presence or addition of one or more other
features, regions, integers, steps, operations, elements,
components, and/or groups thereof.
[0020] Unless otherwise defined, all terms (including technical and
scientific terms) used herein have the same meaning as commonly
understood by one of ordinary skill in the art. It will be further
understood that terms, such as those defined in commonly used
dictionaries, should be interpreted as having a meaning that is
consistent with their meaning in the context of the relevant art
and the present disclosure, and will not be interpreted in an
idealized or overly formal sense unless expressly so defined
herein.
[0021] In one aspect, there is provided a method for purifying a
polylactic acid or a derivative thereof, or a salt thereof.
Particularly, the method enables preparation of a polylactic acid
or a derivative thereof, or a salt thereof, having a lactone
content of 1.0 wt % or less and a content of metal in an
organometal catalyst of 50 ppm or less, particularly 20 ppm or
less.
[0022] The lactone monomers, and hydrolyzates and low-molecular
weight oligomers thereof are decomposed easily in vivo and in an
aqueous solution, resulting in a drop in pH. Thus, decomposition of
the polymer is accelerated and the stability of a drug contained in
the polymer is affected thereby, resulting in generation of
impurities. In addition, the organometal catalyst contained in the
polymer as a foreign material accelerates hydrolysis of the
polymer, resulting in a decrease in the molecular weight of the
polymer, and thus a drop in pH. When the hydrolysis of the polymer
is accelerated by the organometal catalyst, the polymer used in a
formulated composition as a drug carrier is hindered in continuous
drug release. Therefore, the polymer may cause undesirably earlier
drug release, making it difficult to control the drug release rate.
Therefore, in drug delivery systems using a polylactic acid or a
derivative thereof, or a salt thereof, it is required to control
the amount of monomers and low-molecular weight oligomers and the
organometal catalyst content in order to control the drug release
rate and to prevent generation of impurities.
[0023] When the lactone monomer content is greater than 1.0 wt %,
decomposition of the polymer is accelerated to adversely affect the
stability of the drug contained in the polymer, leading to
generation of impurities. In addition, when the content of the
metal in an organometal catalyst is in excess of 50 ppm, hydrolysis
of the polymer is accelerated and pH is decreased, resulting in
failure of continuous drug release.
[0024] Therefore, disclosed herein is a method for purifying a
polylactic acid or a derivative thereof, or a salt thereof by
effectively removing unreacted monomers, oligomers or an
organometal catalyst remaining in crude polymer during the
preparation thereof, so that a highly purified polymer may be
provided.
[0025] The term `polyactic acid` means a polymer polymerized from
lactide or lactic acid, wherein the polylactic acid may be
end-capped with a hydroxyl or carboxyl group.
[0026] In another embodiment, the `polyactic acid derivative` may
be at least one compound(s) selected from the group consisting of
polylactide, polyglycolide, polymandelic acid, polycaprolactone,
polydioxane-2-one, polyaminoacids, polyorthoesters, polyanhydrides
and copolymers thereof. Particularly, the polylactic acid
derivative may include polylactide, polyglycolide, polycaprolactone
or polydioxane-2-one.
[0027] Particular examples of a polylactic acid or a derivative
thereof may include at least one compound(s) selected from the
group consisting of polylactic acid, copolymers of lactic acid with
mandelic acid, copolymers of lactic acid with glycolic acid,
copolymers of lactic acid with caprolactone, and copolymers of
lactic acid with 1,4-dioxane-2-one.
[0028] Unless the context clearly indicates otherwise, it is
understood that the term `polyactic acid` or `polyactic acid
derivative` when used in this specification, means polylactic acid
and polylactic acid derivative collectively because there is no
differences in the purification method between polylactic acid and
polylactic acid derivative.
[0029] In still another embodiment, the salt of polylactic acid or
polylactic acid derivative may include an alkali metal salt of
polylactic acid or polylactic acid derivative. Particularly, the
alkali metal salt may include a metal ion salt of monovalent metal
ion selected from sodium, potassium and lithium.
[0030] In one example embodiment, the polylactic acid or a
derivative thereof, or a salt thereof may have a number average
molecular weight of 500-20,000 daltons, specifically 500-10,000
daltons, and more specifically 500-5,000 daltons.
[0031] Particular embodiments of methods for preparing a polylactic
acid or a derivative thereof as a starting material will be
explained hereinafter.
[0032] In one embodiment, a ring opening polymerization process is
carried out using lactone, such as L-lactide or D,L-lactide, as
monomer. As an initiator, a hydroxyl group-containing compound may
be used. For example, an alcohol with a high boiling point may be
used. Particular examples of such alcohols include lauryl alcohol,
1,6-hexanediol, etc.
[0033] In addition to the initiator, an organometal catalyst is
used so that the monomers are polymerized by the hydroxyl groups of
the initiator. Particularly, when preparing a polylactic acid
derivative for medical use, stannous octoate, approved by FDA as a
medically acceptable catalyst, is generally used as a catalyst. The
ring opening polymerization process is used for preparing a
high-molecular weight polylactic acid derivative. The polylactic
acid derivative prepared from the ring opening polymerization
process still contains unreacted monomers and the organometal
compound added as a catalyst.
[0034] In another embodiment, condensation polymerization is
carried out using free acid, such as lactic acid. The condensation
polymerization process is useful for preparing polylactic acid with
a low molecular weight. This is because the condensation
polymerization process does not allow easy and effective removal of
water produced as a byproduct. To remove water as a byproduct, melt
condensation polymerization may be carried out under a
high-temperature vacuum condition. Otherwise, solution
polymerization may be carried out using a water immiscible organic
solvent in a reactor equipped with a Dean-Stark trap. The
condensation polymerization process using lactic acid is useful for
preparing a polylactic acid or derivatives thereof having a low
molecular weight of 5,000 daltons or less. In this case, the
polymerization may be performed without adding any catalyst.
Polymerization of lactic acid via polycondensation provides
polylactic acid still containing unreacted lactic acid and lactide
generated under the high-temperature vacuum condition.
[0035] The polylactic acid or a derivative thereof, or a salt
thereof obtained by the above-mentioned ring opening polymerization
or condensation polymerization process includes a certain amount of
unreacted monomers, i.e., lactide and lactic acid, oligomers
thereof and organometal catalyst. The monomers, oligomers and
organometal catalyst contained in the resultant crude polymer may
be easily decomposed in vivo and in an aqueous solution, resulting
in a drop in pH (acidification). As a result, decomposition of the
polymer may be accelerated. When the hydrolysis of the polymer is
accelerated by such impurities, the polymer used in a formulated
composition as a drug carrier is hindered in sustained drug release
and causes undesirably earlier drug release, making it difficult to
control the drug release rate.
[0036] Therefore, disclosed herein is a method for purifying a
polylactic acid or a derivative thereof, or a salt thereof by
effectively removing byproducts or impurities generated during the
preparation thereof, so that a polylactic acid or a derivative
thereof, or a salt thereof with high purity may be provided.
[0037] According to one embodiment of the method for purifying a
polylactic acid or a derivative thereof, or a salt thereof
disclosed herein, the method includes: dissolving a polylactic acid
or a derivative thereof, or a salt thereof into a water-miscible
organic solvent; adding water or an aqueous alkali metal salt
solution to the solution of polymer dissolved in the organic
solvent, followed by mixing; subjecting the mixture to phase
separation to remove water and to recover the organic solvent
layer; and removing the organic solvent from the organic solvent
layer to recover the polymer.
[0038] The method disclosed herein may be applied to polylactic
acid or a derivative thereof with a low molecular weight.
[0039] First, a polylactic acid or a derivative thereof, or a salt
thereof is dissolved into a water-miscible organic solvent to
provide a polymer solution. For example, the organic solvent may be
one capable of solubilizing the polymer and may include a
water-compatible organic solvent having a boiling point of
100.degree. C. or lower. Particularly, the organic solvent may
include acetone or acetonitrile.
[0040] Next, water or an aqueous alkali metal salt solution is
added to the solution of polymer dissolved in the organic solvent.
Particularly, water or an aqueous alkali metal salt solution is
gradually added to the organic solvent in which a polylactic acid
or a derivative thereof, or a salt thereof is dissolved to
hydrolyze unreacted monomers and oligomers. For example, the
aqueous alkali metal salt solution has a concentration of 0.05-0.1
g/mL. Although the amount of water or the aqueous alkali metal salt
solution is determined by the unreacted monomer content and the
amount of the organic solvent, water or the aqueous alkali metal
salt solution may be added in an amount corresponding to 0.5-2
times of the volume of the organic solvent.
[0041] In addition to the above role of the aqueous alkali metal
salt, when the aqueous alkali metal salt solution is added to the
polymer solution, it is possible to obtain a polylactic acid salt,
a polylactic acid whose carboxy groups are replaced with alkali
metal carboxylate, from a polylactic acid having carboxylic acid
group at an end at this step. For example, the alkali metal salt
may be at least one metal salt(s) selected from the group
consisting of sodium bicarbonate, sodium carbonate, potassium
bicarbonate, potassium carbonate and lithium carbonate. The
particular type of alkali metal salt determines the metal ionically
bonded with the carboxyl group of the polylactic acid salt
end-capped with a carboxyl group such as the compound of Chemical
Formula 2 or 3. Particularly, the aqueous alkali metal salt
solution may be an aqueous sodium bicarbonate or potassium
bicarbonate solution. Meanwhile, when adding water to the polymer
solution, polylactic acid end-capped with a carboxylic acid having
proton is provided.
[0042] In one example embodiment, the mixing operation may be
carried out by agitating the mixture at 40-100.degree. C. for 10
minutes to 24 hours. Particularly, the mixing operation includes
agitating the mixture at 60-80.degree. C. for 2-6 hours. During the
agitation under heating, low-molecular weight polylactic acids and
monomers are hydrolyzed. When using an alkali metal salt,
neutralization occurs between the alkali metal salt, and
low-molecular weight polylactic acids and monomers to provide salt
compounds. Since the salt compound has high solubility to an
aqueous solution, it facilitates purification via phase separation.
The heating temperature and agitation time in the mixing operation
are designed to facilitate hydrolysis and salt formation. For
example, if the heating temperature is too high, the polylactic
acid may undergo hydrolysis after the preparation thereof, leading
to a decrease in molecular weight.
[0043] Then, the mixture is left to be phase-separated. In another
example embodiment, the phase separation may be improved by adding
a salt to the mixture so that the mixture is separated into an
organic solvent layer and an aqueous layer. For example, the salt
may include sodium chloride or potassium chloride. The separation
using a salt may be carried out, for example, by adding sodium
chloride to the mixture after the hydrolysis so that the solution
is separated into the water-miscible organic solvent layer and an
aqueous layer. After the phase separation, only the purified
polymer is dissolved in the organic solvent layer, while the salt
compound, alkali metal salt, unreacted monomers and oligomers and
organometal catalyst are dissolved in the aqueous layer. When the
polylactic acid or a derivative thereof is end-capped with a
carboxylic acid having proton, phase separation may occur without
adding any salt, because the polymer is not dissolved in water.
[0044] After the phase separation, the organic solvent is removed
from the organic solvent layer to recover the polymer. For example,
the organic solvent is removed from the organic solvent layer via
fractional distillation. For example, the fractional distillation
may be carried out at a temperature of 60-80.degree. C.
[0045] In still another embodiment, the method may further include,
after removing the solvent to recover the polymer: dissolving the
recovered polymer into an anhydrous organic solvent, followed by
filtering, to obtain a polymer-containing organic solvent; and
removing the anhydrous organic solvent from the polymer-containing
organic solvent.
[0046] For example, the anhydrous organic solvent may be anhydrous
acetone or anhydrous acetonitrile.
[0047] In the filtering operation to obtain the polymer-containing
organic solvent, a polylactic acid or a derivative thereof, or a
salt thereof, from which the originally used water-miscible organic
solvent is removed, is dissolved back into the anhydrous organic
solvent. In this manner, the polymer is dissolved in the anhydrous
organic solvent, while a small amount of salt compound such as
sodium chloride or sodium bicarbonate, and alkali metal salt are
precipitated. The precipitated compounds are removed by centrifugal
separation or filtering.
[0048] Then, when removing the anhydrous organic solvent from the
polymer-containing organic solvent, the polymer, from which the
salt such as sodium chloride is removed, is further subjected to
distillation to remove the organic solvent. For example, the
distillation may be carried out at a temperature of 60-80.degree.
C. After removing the organic solvent, the purified polymer may be
provided.
[0049] In a particular embodiment, the polylactic acid or a
derivative thereof, or a salt thereof disclosed herein may include
a monomer represented by Chemical Formula 1:
##STR00001##
[0050] wherein
[0051] Y represents H, methyl or phenyl; and
[0052] A represents an integer from 5 to 300.
[0053] In a more particular embodiment, the polylactic acid or a
derivative thereof, or a salt thereof may be represented by
Chemical Formula 2 or 3:
HO--[R.sup.1].sub.l[R.sup.2].sub.m--C(.dbd.O)--O-M [Chemical
Formula 2]
[HO--[R.sup.1].sub.l[R.sup.2].sub.m--C(.dbd.O)--O-].sub.n-A
[Chemical Formula 3]
[0054] wherein
[0055] R.sup.1 represents --C(.dbd.O)--O--CHZ--;
[0056] R.sup.2 represents --C(.dbd.O)--O--CHY--,
--C(.dbd.O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2-- or
--C(.dbd.O)--O--CH.sub.2CH.sub.2OCH.sub.2--;
[0057] Z and Y independently represent H, methyl or phenyl;
[0058] l and m represent an integer from 0 to 150, with the proviso
that both cannot represent 0 at the same time;
[0059] M represents H, Na, K or Li;
[0060] A represents a diol or a polyol compound containing 3-12
hydroxyl groups; and [0061] n represents an integer from 2 to 12
and is the same as the number of hydroxyl groups contained in
A.
[0062] More particularly, the compound containing 2-12 hydroxyl
groups may include a single compound, such as an alcohol, diol
compound, glycerol, pentaerythritol or xylitol, or a polymeric
compound, such as polyethylene glycol or monomethoxypolyethylene
glycol.
[0063] In another aspect, there is provided a polylactic acid or a
derivative thereof, or a salt thereof with high purity. In one
embodiment, the polylactic acid or a derivative thereof, or a salt
thereof has a lactone monomer content of 1.0 wt % or less and a
content of metal in an organometal catalyst of 50 ppm or less,
particularly 20 ppm or less.
[0064] In still another aspect, there is provided a pharmaceutical
composition including a polylactic acid or a derivative thereof, or
a salt thereof. The polymer has excellent biocompatibility and is
not harmful to the human body, and thus may be used as a drug
carrier in various forms. In addition, the polymer may be modified
in terms of molecular weight or copolymer constitution to control
drug release rate. To accomplish this, highly purified polymer is
required.
[0065] The pharmaceutical composition may further include
pharmaceutical adjuvants, such as a preservative, stabilizer,
hydrating agent or emulsification accelerator, osmotic
pressure-adjusting salt and/or buffer, and other therapeutically
effective materials. In addition, the pharmaceutical composition
may be formulated into various oral or parenteral administration
forms depending on administration route according to a method
generally known to those skilled in the art.
[0066] The examples and experiments will now be described. The
following examples and experiments are for illustrative purposes
only and not intended to limit the scope of this disclosure.
Preparation Example 1
Synthesis of D,L-polylactic acid(PLA-COOH) via polycondensation
[0067] First, 1,000 g of D,L-lactic acid was introduced into a
2,000 mL three-necked round bottom flask and an agitator was
mounted to the flask. Next, the flask was treated for 1 hour while
being heated in an oil bath at 80.degree. C. and depressurized to
25 mmHg with a depressurization aspirator to remove an excessive
amount of water.
[0068] Then, the temperature was increased to 160.degree. C. and
the reaction was continued for 6 hours under a reduced pressure of
5-10 mmHg, before the reaction was terminated. After the reaction,
646 g of crude polylactic acid was obtained. The polylactic acid
was analyzed by NMR and the results are shown in FIG. 1.
Preparation Example 2
Synthesis of D,L-polylactic acid (PLA-COOH) via ring opening
polymerization
[0069] First, 500 g of D,L-lactide was introduced into a one-neck
flask and vacuum dried at 50.degree. C. for 4 hours. After the
flask was cooled to room temperature, tin octoate catalyst (250 mg,
0.05 wt %) dissolved in toluene (0.5 mL) and 62.5 g of 1-dodecanol
were introduced to the flask, and vacuum dried for 2 hours. The
flask was purged with nitrogen gas, and polymerization was
performed at 130.degree. C. for 6 hours. After the polymerization,
380 g of crude polylactic acid was obtained.
Comparative Example 1
Purification of D,L-polylactic Acid (PLA-COOH)
[0070] First, 100 mL of acetone was added to 100 g of the
polylactic acid obtained from Preparation Example 1 to dissolve the
polymer. Next, the polymer solution was gradually added to 1,000 mL
of distilled water to precipitate the polymer. The precipitated
polymer was filtered and washed with 500 mL of distilled water
twice. To remove an excessive amount of water, the polymer was
vacuum dried at 90.degree. C. for 2 hours. After drying, 87 g of
purified polylactic acid was obtained. The purified polylactic acid
was analyzed by NMR and the results are shown in FIG. 2.
Comparative Example 2
Purification of D,L-polylactic Acid (PLA-COOH)
[0071] First, 100 mL of methylene chloride was added to 100 g of
the polylactic acid obtained from Preparation Example 2 to dissolve
the polymer. Next, the polymer solution was gradually added to
1,000 mL of diethyl ether to precipitate the polymer. Then, the
precipitated polymer was filtered. The polymer was vacuum dried at
room temperature. After drying, 66 g of purified polylactic acid
was obtained.
Example 1
Purification of D,L-polylactic Acid (PLA-COOOH)
[0072] First, 200 mL of acetonitrile was added to 100 g of
polylactic acid obtained from Preparation Example 1 to dissolve the
polymer. Next, 200 mL of distilled water was added to the polymer
solution, and the mixture was agitated at 60.degree. C. under 100
rpm for 2 hours. After the two solvent layers were separated from
each other at room temperature, the organic solvent layer was
isolated. Then, the organic solvent layer was washed with 100 mL of
distilled water to cause additional phase separation, and then the
organic solvent layer was collected. The organic solvent layer was
subjected to fractional distillation at 80.degree. C. under vacuum
to remove the organic solvent. As a result, 73 g of purified
polylactic acid was obtained. The purified polylactic acid was
analyzed by NMR and the results are shown in FIG. 3.
Example 2
Synthesis and Purification of Sodium Salt of D,L-polylactic Acid
(PLA-Coona)
[0073] First, 150 mL of acetonitrile was added to 100 g of the
polylactic acid obtained from Preparation Example 1 to dissolve the
polymer. Next, 150 mL of aqueous sodium bicarbonate solution (0.1
g/mL) was gradually added to the polymer solution, and the mixture
was agitated at 60.degree. C. under 100 rpm for 2 hours. Then, 15 g
of sodium chloride was added thereto at room temperature and
dissolved with agitation. The two solvent layers were separated
from each other using a separation funnel and the aqueous layer was
discarded.
[0074] Then, 100 mL of distilled water and 10 g of sodium chloride
were added to the remaining organic solvent layer and dissolved
therein with agitation. The two solvent layers were separated again
using a separation funnel to collect the organic solvent layer. The
organic solvent layer was subjected to fractional distillation at
80.degree. C. under vacuum for 2 hours to completely remove the
organic solvent and distilled water.
[0075] After that, 150 mL of anhydrous acetone was added thereto to
dissolve the polymer, and the non-dissolved precipitate was
filtered off. The resultant polymer solution was subjected to
fractional distillation at 80.degree. C. under vacuum for 2 hours
to remove acetone. As a result, 69 g of purified sodium salt of
polylactic acid was obtained. The purified sodium salt of
polylactic acid was analyzed by NMR and the results are shown in
FIG. 4.
Example 3
Synthesis and Purification of Sodium Salt of D,L-polylactic Acid
(PLA-Coona)
[0076] Example 2 was repeated, except that 100 g of the polylactic
acid obtained from Preparation example 2 was used, to obtain 63 g
of purified sodium salt of polylactic acid.
Test Example 1
Comparison of Purification Quality
[0077] The polylactic acid or derivatives thereof, or salts
thereof, prepared or purified according to Preparation Examples 1
and 2, Comparative Examples 1 and 2, and Examples 1, 2 and 3, were
analyzed to determine the molecular weight, lactide content and
organometal catalyst content in each polymer.
[0078] To determine the molecular weight and lactide content of
each polymer, .sup.1H-NMR analysis was carried out to obtain
intensity of hydroxyl groups as terminal groups of polylactic acid.
Then, the molecular weight and lactide content were calculated from
the intensity. Sn content was analyzed by induction coupled plasma
(ICP) emission spectroscopy.
[0079] The test results are shown in Table 1.
TABLE-US-00001 TABLE 1 Molecular Lactide content Sn content weight
(Mn) (wt %) (ppm) Preparation Example 1 1,080 4.6 -- Comparative
Example 1 1,200 1.8 -- Example 1 1,260 0.5 -- Example 2 1,285 Not
detected -- Comparative Example 2 1,245 5.2 152 Example 3 1,312 0.1
8.5
[0080] As can be seen from Table 1, when purifying D,L-polylactic
acid having a relatively low molecular weight, lactide is not
completely removed by the known method based on a
solvent/non-solvent process (Comparative Example 1). Also, in this
case, the purified D,L-polylactic acid shows a relatively small
increase in molecular weight as compared to the original sample
(Preparation Example 1). In addition, when purifying D,L-polylactic
acid according to Comparative Example 2, the purified polymer still
has a high lactide content and includes a large amount of
organometal catalyst remaining after the purification.
[0081] On the contrary, according to Examples 1, 2 and 3, the
purified polylactic acid has significantly low lactide content and
shows a relatively large increase in molecular weight. In addition,
Example 3 demonstrates that the organometal catalyst is effectively
removed from the purified polylactic acid. Therefore, the above
results demonstrate that the method disclosed herein provides a
highly purified polylactic acid, or a derivative thereof, or a salt
thereof.
INDUSTRIAL APPLICABILITY
[0082] The polylactic acid or a derivative thereof, or a salt
thereof disclosed herein may be applied to various medical and drug
carrier systems, or the like.
[0083] While the exemplary embodiments have been shown and
described, it will be understood by those skilled in the art that
various changes in form and details may be made thereto without
departing from the spirit and scope of this disclosure as defined
by the appended claims.
[0084] In addition, many modifications can be made to adapt a
particular situation or material to the teachings of this
disclosure without departing from the essential scope thereof.
Therefore, it is intended that this disclosure not be limited to
the particular exemplary embodiments disclosed as the best mode
contemplated for carrying out this disclosure, but that this
disclosure will include all embodiments falling within the scope of
the appended claims.
* * * * *